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Патент USA US2107321

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Patented Feb. 8, 1938
2,107,321?‘
UNITED STATES PATENT OFFHQE
2,107,321
ORGANIC MERCURY COIVIPOUNDS
Carl N. Andersen, Watertown, Mass., assignor
to Lever Brothers Company, a corporation of
Maine
No Drawing. Applicationv January 21, 1935,
Serial No. 2,758
13 Claims.
The present invention relates to the produc
_ tion of certain new organic mercury compounds,
particularly aromatic mercury substituted pyra
zoles and pyrazolones.
5
. It is the object of my invention to produce new
organic mercury compounds useful as germlcides
and for other therapeutic purposes.
More particularly, it is an object of my inven
tion to prepare certain new organic mercury
~-compounds which may be regarded as substituted
derivatives of members of the pyrazole group,
particularly the pyrazolones.
tached to the nitrogen atom or atoms in the ring,
and in some cases also the hydrogen atom or
atoms attached to one or more of the carbon
atoms in the ring,-has been replaced by any 10
monovalent radical except an acidic group, for
cides and at the same time are characterized
by relatively low toxicity and other desirable
967, ?led January 9, 1935.
L'properties.
Examples of substituted pyrazoles of the above
The above mentioned aromatic mercury com
pounds contain the essential radical RHg-, in
which R represents an aromatic structure to a
carbon atom of which the mercury is directly
attached, and may be an aromatic nucleus with
or without side chains. The expression “aro
matic structure” used herein is intended to be
generic and includes an aromatic ‘nucleus with or
without side chains.
The aromatic structure is
of the type in which none of the nuclear or side
chain carbon atoms has direct linkage with any
element other than hydrogen, carbon or mer
cury. R may stand for the phenyl group, C6H5,
or for an aromatic hydrocarbon having a nucleus
similar to the phenyl hydrocarbons, as for ex
de?ned type are:
1,3-dimethyl pyrazole
1,3,5-triphenyl pyrazoline
l-phenyl, Z-methyl pyrazolidine
1,2,3-phenyldimethyl pyrazolidone
and ones that I have found to be useful in pro
ducing particularly interesting aromatic mer
cury compounds are the substituted pyrazolones.
30
Examples of these compounds are:
l-phenyl
razolone-5
l-phenyl
l-phenyl
lonic acid)
attached to mercury, and any side chain carbon
atoms, have their valences satis?ed either by
carbon or hydrogen. Examples are the diphenyl,
rene)‘
2,3-dimethyl ll-dimethylamlno py~
(pyramidon)
B-methyl pyrazolone-5
3-methyl 4-nitro pyrazolone-5 (picro~
l-phenyl 2,3-dimethyl pyrazolone-5 (antipy
tolyl, xylyl and naphthyl groups.
Tartrazine, Schultz
#640
The members ‘of the pyrazole group, which will
here be referred to generally as pyrazoles, and
The preparation of these compounds leads me
to believe, that all the members of this group
#737;
“Colour Index”
40
any one of which may be regarded as a pyrazole,
react in the same manner and can be employed
are:
to produce my novel mercury compounds. The
compounds so prepared have, in greater or lesser,
CH:N
CH:N
NH; pyrazoline, i
pyrazole,
CHzC H
CH :N
pyrazolone, ‘
\
NH; pyrazolidine,
/
CH2.CO
CH2.NH
55 pyrazolidone,
H2.CH:/
CH:.CO
but always in relatively high degree, desirable
antiseptic and germicidal properties. I there
fore regard my invention as generic to and in
eluding this entire group of substituted pyra
zoles.
The general method of preparing these com
pounds consists in reacting together the substi
tuted pyrazole and a compound containing the
NH;
CH2.NH
NH;
CHLCHE
C O.NH
NH; 3,5-diketopymzolidine.
NH
oHwo/
IO Cl
Further examples of the substituted pyrazoles,
ample, polycyclic hydrocarbons, in which all of
the nuclear carbon atoms, other than the one
)
50
The compounds comprising the substituted
members of the pyrazoles, the aromatic mercury
derivatives of which constitute my invention, are 5
those in which at least the hydrogen atom at
ally substituted are neutral (i. e. non-acidic)
such as the alkyl and aromatic.
The aromatic mercury derivatives of the het
erocyclic compounds in which a carboxyl group
is attachedv to one or more ring elements are dis
closed and claimed in my application Serial No.
narily high potency as antiseptics and germi
C
application Serial No. 754,374, ?led November
22, 1934.
example the carboxyl group. - The radicals usu
I have discovered that when certain aromatic
mercury compounds are reacted with substituted
,‘-derivatives of members of the pyrazole group,
compounds are produced which have extraordi
c: Ci
(Cl. 260-43)
aromatic mercury radical of the above mentioned. 55
type. A common solvent for both reacting com_.
ponents is employed.
The compound resulting
The above listed compounds are heterocyclic from the reaction is usually relatively insoluble
imides.- The aromatic mercury derivatives‘ of... as compared with the reacting components and
these- imidesf are disclosed and claimed" in my; upon its precipitation ‘may bea?ltered; washed-and
60
240M321
2
dried. If the compound formed is relatively sol
uble, the solution may be concentrated and the
compound will crystallize out.
The chemistry of the pyrazoles and pyrazolones
solution is complete. The solution is then ?ltered
to remove any insoluble material. To the ?ltrate
is added 14.32 grams of pyramidon (1-phenyl
2,3-dimethyl
4-dimethylamino
pyrazolone-5).
is very complex and sufficient data are not avail
able for a complete understanding of their struc—
No precipitate results at ?rst but on concentra
tion of the solution crystals separate. These are
are different from those of the reacting materials.
However, having disclosed my invention and the
well with warm Water and alcohol
The material melts at 99-105” C.
procedure is duplicated in aqueous
compound results which decomposes
ture and chemical properties under all conditions. separated by ?ltration, Washed and dried. They
The di?iculty in studying these compounds and melt at 145-155° C. Upon further concentration of
their derivatives may be accounted for in part by the mother liquor, another crop of crystals sepa
rate which melt at 170-172" C. The compounds
the ionic migration and the internal rearrange
are phenylmercury derivatives of pyramidon.
ment of the atoms in the molecule under differ
ent conditions, a phenomenon which is character
Example 2
istic of these compounds.
17.64
grams
of
phenylmercury hydroxide is
From my present investigations I am unable’
15
to state the mechanism of the reaction which I dissolved in 2 liters of water and heated until the
solution
is
complete.
The
solution
is
then
?ltered
have employed to produce my novel mercury com
pounds or to assign a de?nite structural formula to remove any insoluble material. 11.48 grams of
l-phenyl 3-methyl pyrazolone-5 is dissolved in
to the compounds produced. I am, however, cer
200
cc. of 75% ethyl alcohol. These two solutions
tain that the aromatic mercury radical or com
are brought together by pouring them into a 20
20 pound is combined in some manner with the sub
stituted pyrazole, because the melting points and third container. A white amorphous solid re
the germicidal values of the compounds produced sults which is separated by ?ltration, washed
novel compounds so that they may be produced
by one skilled in the art, I prefer not to speculate
in assigning any de?nite formulae to the com
pounds produced or in stating in what position
or how the aromatic mercury radical or com
pound is attached to the substituted pyrazole
compound.
The compounds produced will depend in some
instances on the particular aromatic mercury
compound employed as the initial reacting ma
terial, and in some instances on the solvent em
ployed. When an aromatic mercury hydroxide
is used as the reacting material I am inclined to
believe that it is the aromatic mercury radical
thereof that is introduced into the compound.
40 This does not exclude the possibility that the
hydroxyl radical is also introduced. When a sol
uble salt such as the acetate is employed as the
reacting material, I am inclined to believe that
an addition product of some type is formed.
When the same substituted pyrazole is treated
with the hydroxide and also with a soluble salt,
compounds result which have different melting
points. When water is employed as the solvent,
in some instances two compounds having di?'er
ent melting points may be produced. When al
cohol is employed as a solvent, a compound re
sults which has a different melting point than
the compound obtained when water is employed
as the solvent. These phenomena may be ac
counted for by the fact that under di?erent con
ditions thearomatic mercury radical, or the aro
matic mercury compound, will become attached
at different positions in the substituted pyrazole,
or the arrangement of the atoms of the molecule
60 itself may vary under different conditions.
Some
of the compounds I have prepared change in their
properties, particularly their germicidal value,
after standing for some time. This also may be
accounted for by the tendency of compounds of
' this type to undergo inter-molecular rearrange
ments.
The following examples are given as illustrative
of a method by which all of the compounds of
this group may be prepared and as illustrative of
70 representative aromatic mercury
within the scope of my invention:
compounds
Example 1
17.64 grams of phenylmercury hydroxide is ‘dis
and dried.
When the
solution a
at 220° C.
Upon recrystallization it melts at 226° C. The
compounds are the phenyl-mercury derivatives
of l-phenyl 3-methyl pyrazolone-5.
When phenylmercury acetateis substituted for 30
the hydroxide an amorphous material melting at
2251/2" C. is obtained. This compound is believed
to be a phenylmercury acetate addition product
of l-phenyl 3-methyl pyrazolone-5.
Example 3
17.64 grams of phenylmercury hydroxide is
dissolved in 4 liters of Water and heated until
the solution is complete. The solution is then
?ltered to remove any insoluble material. To the 40
?ltrate is added an aqueous solution containing
12.40 grams of antipyrene (l-phenyl 2,3-dimethyl
pyrazolone-5). A precipitate results and after
the mixture is allowed to stand it is ?ltered.
The precipitate is washed well with warm water 45
and dried. It decomposes at 215° C. The com
pound is the phenylmercury derivative of anti
pyrene.
When phenylmercury acetate is allowed
to react with antipyrene a white insoluble ma
terial forms which melts at 227.5° C. This com~
pound is believed to be a phenylmercury acetate
addition product of antipyrene.
Example 4
55
11.66 grams of phenylmercury hydroxide is
dissolved in 4 liters of water and heated until
the solution is complete. The solution is ?ltered
to remove any insoluble material. To the ?l
trate is added 10.56 grams of picrolonic acid 60
(l-phenyl 3-methyl 4-nitro pyrazolone-5) dis
solved in 600 cc. of alcohol.
A yellow precipi
tate forms and at the same time vile odors are
evident. The mixture is allowed to cool, after
which it is ?ltered and the precipitate washed 65
well with warm water and dried.
It softens at
205° C. and decomposes above this temperature.
The compound is phenylmercury picrolonate.
All of the other substituted pyrazoles of this
type may be treated in a manner similar to the 70
above examples to form corresponding aromatic ,
mercury derivatives.
From the speci?c examples
given it will be obvious to one skilled in the art
What procedure is to be followed in producing
Theoretical quantities 75
these other compounds.
75 solved in 4 liters of water and heated until the ~
3.
2,107,321
of reacting materials are generally employed.
In some cases, if desired, approximately 10%
excess of the substituted pyrazole may be em
ployed in order to insure complete conversion of
the aromatic mercury compound.
The operativeness of the process is not found
to depend in any degree upon the temperature
at which the reaction is effected. It is conven
ient to use heat because it facilitates the solu
10 tion of the reacting components and speeds the
reaction, but the process can be carried out at
I claim:
1. An aromatic mercury substituted pyrazole
in which the radical RHg-islinked to a substi
tuted pyrazole,. where R represents an aromatic
structure to the carbon atom of which the mer
curyis directly attached and in. which none of the
carbon atoms has direct linkage with any ele
ment other than hydrogen, carbon and mercury,
and where the substituted pyraz'ole has any hy
drogen attached to nitrogen replaced by a mono— 10
valent hydrocarbon radical.
any temperature, for example, room tempera
' 2. An aromatic mercury substituted pyrazolone
ture. Similarly, the process may be carried out
in any mutual solvent. Water is usually em
in which the radical RHg—is linked to a sub
stituted pyrazolone, where R represents an arc
matic structure to the carbon atom of which the
mercury is directly .attached and in which none
of the carbon atoms has direct linkage with any
element other than hydrogen, carbon and mer
cury, and where the substituted pyrazolone has at
ployed for reasons of convenience when both re~
acting components are water-soluble, but if not,
other solvents, such as the alcohols or acetone
or mixtures of these with each other or with
water may be employed. A difference in solvent
and temperature does not affect the operative
ness of the process but may affect the product
that is formed. However, as all these compounds
possess germicidal properties I regard them as
within the scope of my invention.
All of the compounds produced as above de
scribed are characterized by extraordinarily high
potency as germicides. Tests to determine the
efficacy of certain of them in killing B. typhosus
and Staph. aureus were carried on under the
least the hydrogen attached to nitrogen replaced 20
by a monovalent hydrocarbon radical.
3. An aromatic mercury substituted pyrazolone
in which the radical RHg—is linked to a substi=
tuted pyrazolone, where'R represents an aromatic
structure to the carbon atom of which the mer
cury is directly attached and in which none of the
carbon atoms has direct linkage with any ele
ment other than hydrogen, carbon and mercury,
and where the substituted pyrazolone has the hy
drogen atom attached to the nitrogen atom and a hydrogen atom attached to a carbon atom re?
following conditions:
Aqueous solutions of varying dilutions from
140,000 upward until killing ceased, were
placed by monovalent hydrocarbon radicals.
made up.
These dilutions were employed in the conduct
in which the radical RHg-is linked to a substi
of the tests by the following methods:
Circular 198, U. S. Dept. of Agriculture Dec.
1931, described as F. D. A. Method against Eber
thella typhi (typhoid bacillus) at 37° C. and F.
D. A. Special method against Staph. am‘eus
40 at 37° C.
As illustrative of the potency of the compounds,
the killing power of the following compounds is
given merely as illustrative:
The ?gures represent the maximum dilutions
at which killing in 15 minutes resulted:
B. fyphosus
Staph. IZ'HTB'HS
Phenylmercury l-phenyl ihnethyl
pyrazolone~5 ____________________ ..
In alcohol .................. . .
1:372. 000
1:372. 000
1:100, 000
1:45, 000
1:288, 000
1:252, 000
l'henylmercury l-p h e n y 1
methyl py
mlonc-5. _ _ .
In alcohol _________________________ __
1:70, 000
l :40, 000
1:80, 000
1:40, 000
Phenylmercury picrolonate (in ace
tone) ____________________________ __
4. An aromatic mercury substituted pyrazolone
tuted pyrazolone, where R represents an aromatic 35
structure to the carbon atom of which the mer~
cury is directly attached and in which none of the
carbon atoms has direct linkage with any element
other than hydrogen, carbon and mercury, and
where the substituted pyrazolone has the hydro~ 40
gen atom attached to the nitrogen atom and hy
dro-gen atoms attached to a. plurality of carbon
atoms
replaced by monovalent hydrocarbon
radicals.
'
5. A phenylmercury substituted pyrazole in
which the radical CsHsHg-iS linked to a sub
stituted pyra‘zole and in which the substituted
pyrazole has any hydrogen attached to nitrogen
replaced by a monovalent hydrocarbon radical.
6. A phenylmercury substituted pyrazole in
which the radical C6H5Hg-is linked to a substi~
tuted pyrazole and in which the substituted pyra
zole has any hydrogen attached to nitrogen and
a hydrogen attached to at least one of the car
bon atoms replaced by a monovalent hydrocarbon
vi Ll
Inaddition to their high germicidal value, all
of these compounds are characterized by rela~
tively low toxicity. Because of these properties
it is possible to use them in extreme dilutions and
in many situations where :nown germicides, be
cause of toxic or other undesired properties, can
not be employed.
They may be used externally
and locally, and in some cases administered in—
ternally with satisfactory results from the germi
cidal standpoint and without harmful effect to
the body or its functions.
The compounds retain their germicidal activ
ity when incorporated in soap and various
menstrums employed in preparing germicidal
compositions.
When these new compounds are to be used
directly as germicides they may be employed in
aqueous or other solutions or they may be formed
radical.
‘
7. A phenylmercury substituted pyrazolev in
which the radical CsI-IsI-Ig—is linked to a sub
stituted pyrazole and in which the substituted
pyrazole has any hydrogen attached to nitrogen fill
and hydrogen atoms attached to a plurality of
carbon atoms replaced by monovalent hydrocar
bon radicals.
8. A phenylmercury substituted pyrazolone in
which the radical C6H5Hg-is linked to a sub
stituted pyrazolone and in which the substituted
pyrazolone has at least the hydrogen atom at
tached to the nitrogen atom replaced by a mono
a
valent hydrocarbon radical.
9. A phenylmercury substituted pyrazolone in
which the radical CeHsi-Ig-iS linked to a substi
tuted pyrazolone and in which the substituted
into various preparations such as mouth washes,
pyrazo-lone has the hydrogen atom attached to
tooth pastes, soaps, ointments, etc.
the nitrogen atom and a hydrogen atom attached 76
4
2,107,321
to a carbon atom replaced by monovalent hydro
carbon radicals. '
10. A phenylmercury subsituted pyrazolone in
which the radical C6H5Hg—is linked to a sub
stituted pyrazolone and in which the substituted
pyrazolone has the hydrogen atom attached to
the nitrogen and the hydrogen atoms attached
to a plurality of carbon atoms replaced by mono
valent hydrocarbon radicals.
11. vA phenylmercury substituted pyrazolone in
which the radical CsH5Hg—-is linked to l-phenyl
2,3-dimethyl 4-dimethylamino pyrazolone-5.
12. A phenylmercury substituted pyrazolone in
which the radical CsHsHg-is linked to l-phenyl
3-methyl pyrazolone-5.
13. A phenylmercury substituted pyrazolone in
which the radical CsH5Hg--is linked to l-phenyl
2,3-dimethyl pyrazo10ne-5.
CARL N. ANDERSEN.
10
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